Cell division, cell growth and cell differentiation are complex processes which are regulated to a great extent by phosphorylation/dephosphorylation events. Thus, protein kinases and phosphatases play a major role in cell regulation. The members of the protein kinase family are known to modulate the activity of a wide variety of proteins, including kinases, phosphatases, transcription factors, cyclins, metabolic enzymes and structural proteins, among others. The cell cycle is regulated, at least in part, by a subfamily of protein kinases called cyclin-dependent kinases (CDKS). These protein kinases contain a catalytic domain that requires the association of a regulatory subunit called cyclin, which is necessary for the kinase activity of the complex. Cyclin/CDK complexes have been shown to be required at different points of the cell cycle. In vertebrates, CDK2 is required for DNA synthesis probably associated to cyclin E. The transition from interphase to mitosis requires the activity of CDC2, which is associated to cyclin B. Moreover, CDK4/ and CDK6/D-type cyclin complexes appear to link growth factor stimulation to cell cycle progression. The role of CDK5 in the cell cycle is controversial. Although this kinase associates with D-type cyclins, it is expressed at high levels in terminally differentiated neuronal cells and appears to be involved in the phosphorylation of neurofilaments.
Orderly progression through the cell cycle in yeast requires the association of a single cyclin-dependent kinase (cdk), p34/cdc2/CDC28, with cyclins to form active phosphorylating complexes which regulate both the G1/S and G2/M transitions. With the discovery and characterization of several murine and human cdc2-related kinases, it has become apparent that mammalian cell cycle systems operate under a much higher degree of complexity. Several different cyclin-cdk complexes have been found active at different stages in the cell cycle.
Components of the cell cycle regulatory machinery have been found to be involved in several human cancers. Cyclin dependent kinases, their regulatory subunits or cyclins, cyclin-dependent kinase inhibitors, as well as the associated tumor suppressor proteins p53 and pRb, have been found to be deregulated or mutated in numerous human tumors. The transforming activity of DNA tumor virus proteins E1A, SV40 large T, and E7 is exerted, at least in part, through their binding of the growth suppressor pRb and consequent release of E2F. In addition, E1A has been shown to bind to cyclin A/cdk2 complexes, providing the first direct link between the cell cycle and a transformed phenotype.
Cell proliferation disorder is implicated in certain diseases such as psoriasis, vascular disease and cancer. There is a need to identify compounds which inhibit the undesirable cell proliferation associated with cancer. Specifically, safe and effective compounds are sought which reduce the abnormal cell proliferation which is characteristic of cancer by interfering with the molecular signals that participate in the unrestrained reproduction and multiplication of malignant cells. Specifically, safe and effective compounds are sought which interfering with the molecular signals that participate in the unrestrained reproduction and multiplication of cells whose abnormal cell proliferation characteristic of diseases, disorders and conditions such as cancer, psoriasis and vascular diseases and disorders.